Mechanisms Underlying Contextual Induction of Muscle Thermogenesis While obesity is clearly a major public health concern in the US, it has proven to be stubbornly resistant to prevention and treatment. While investigating mechanisms underlying endogenous amplification of energy expenditure, we identified a pathway in the brain that increases sympathetic nervous system (SNS) activity to skeletal muscle, impacting molecular pathways that modulate muscle energy uptake and use. We hypothesize that this increased caloric use promotes leanness by enhancing energy expended during physical activity, increasing muscle thermogenesis where caloric energy is ultimately dissipated as heat. Recently, we discovered that exposure to predator odor (ferret) rapidly and robustly increases muscle thermogenesis in rats. This persists when activity is held constant, and it translates into a significant increase in energy expenditure. Here, we will investigate the neural pathway that is responsible for this effect. Frist, we will demonstrate that predator odor enhances weight loss during energy restriction, and activates muscle thermogenesis even in the absence of interscapular brown adipose tissue or beta-3 adrenergic receptor activation. Second, we hypothesize that activation of the ventromedial hypothalamus (VMH) and of steroidogenic factor-1 neurons within the VMH are critical for the ability of predator odor to activate muscle thermogenesis and enhance activity-related energy expenditure. We will use a neural inhibition tool?designer receptors exclusively activated by designer drugs (DREADDs), delivered using a viral vector?to suppress the activity of the VMH in rats, or of steroidogenic factor-1 neurons within the VMH of mice, to demonstrate the role of this cell population in the modulation of muscle metabolism and energy expenditure by predator odor. Lastly, we hypothesize that the SNS is activated by exposure to the predator odor, and that blocking the activity of beta adrenergic receptors will decrease the metabolic response to predator odor. These studies may uncover a novel mechanism for weight loss through enhanced muscle calorie use, and provide opportunities to enhance undergraduate research training in our laboratory.